REVIEW

Immunological mechanisms for desensitization and tolerance

in food allergy
Rima Rachid & Dale T. Umetsu
Received: 1 May 2012 / Accepted: 9 July 2012
#Springer-Verlag 2012
Abstract Food allergy is a major public health concern in
westernized countries, estimated to affect 5 % of children
and 34 % of adults. Allergen-specific immunotherapy for
food allergy is currently being actively evaluated, but is still
experimental. The optimal protocol, in terms of the route of
administration of the food, target maintenance dose, and
duration of maintenance therapy, and the optimal patient
for these procedures are still being worked out. The mech-
anisms underlying successful food desensitization are also
unclear, in part, because there is no standard immunotherapy
protocol. The mechanisms involved, however, may include
mast cell and basophil suppression, development of food-
specific IgG4 antibodies, reduction in the food-specific IgE/
IgG4 ratio, up-regulation and expansion of natural or induc-
ible regulatory T cells, a skewing from a Th2 to a Th1
profile, and the development of anergy and/or deletion in
antigen-specific cells. Additional studies are required to
elucidate and understand these mechanisms by which de-
sensitization and tolerance are achieved, which may reveal
valuable biomarkers for evaluating and following food al-
lergic patients on immunotherapy.
Keywords Food allergy
.
Immunotherapy
.
Desensitization
.
Tolerance
Abbreviations
DBPCFC Double-blind placebo-controlled
food challenge
iT
Regs
Inducible regulatory T cells
IT Immunotherapy
mAb Monoclonal antibody
nT
Regs
Natural regulatory T cells
OFC Oral food challenge
OIT Oral immunotherapy
SIgA Secretory IgA
SLIT Sublingual immunotherapy
SPT Skin prick test
Syk Spleen tyrosine kinase
T
Regs
Regulatory T cells
Introduction
Food allergy is a major public health concern in westernized
countries, estimated to affect 5 % of children and 34 % of
adults [1]. Over the past decade, the prevalence of food
allergies has increased markedly [2]. Approximately 90 %
of allergic reactions to food are secondary to the big 8
allergenic foods, namely, milk, egg, peanut, soy, wheat, tree-
nuts, fish, and shellfish [3]. Peanut allergy alone likely
exceeds 1 % of school-aged children in the UK and the
USA [4, 5]. Many food allergies are spontaneously out-
grown with time; most children outgrow their milk and
egg allergy without treatment by the end of the first or
second decade of life [6, 7]. On the other hand, it is esti-
mated that less than 20 % of patients with peanut allergy
will become tolerant to peanut with time [8]. This is of
major concern, given that peanut and tree-nut allergy ac-
count for the majority of near fatal and fatal anaphylactic
reactions to food [9, 10].
This article is published as part of the Special Issue on Food Allergy
[34:6].
R. Rachid
:
D. T. Umetsu (*)
Karp Laboratories, Division of Immunology and Allergy,
Boston Childrens Hospital,
Rm 10127, One Blackfan Circle,
Boston, MA 02115, USA
e-mail: dale.umetsu@childrens.harvard.edu
R. Rachid
:
D. T. Umetsu
Harvard Medical School,
Boston, MA, USA
Semin Immunopathol
DOI 10.1007/s00281-012-0333-9
The currently accepted standard of care for patients with
food allergies consists of strict avoidance of the food, nutri-
tional counseling, and constant preparedness for treatment
in the event of accidental ingestion with antihistamines and/
or injectable epinephrine. Unfortunately, this approach neg-
atively affects the quality of life for many patients and their
family, as it leads to heightened anxiety from the fear of
accidental ingestion, and limits participation in social events
and school activities [11, 12]. In addition, up to 4075 % of
patients have accidental food ingestions over a 110-year
period, with exposures commonly occurring in schools, day
care, restaurants, or other food establishments [11, 1316].
There is an obvious need for new therapeutic modalities that
would either cure food allergy or at least allow patients to
tolerate a defined quantity of food, thereby eliminating the
possibility, or at least reducing the severity, of reactions
upon accidental ingestion.
Food immunotherapy as an approach for food allergy is
currently being actively investigated. As with inhaled
allergen-specific immunotherapy (allergy shots), food
immunotherapy is performed by the administration of in-
creasing doses of an allergen extract, followed by mainte-
nance dosing for a currently undefined duration of time.
Allergen-specific immunotherapy has been shown to be
effective for many allergic problems (e.g., allergic rhinitis,
bee venom allergy, and drug allergy). The mechanisms by
which allergen-specific immunotherapy, which has been
used for a century for allergic rhinitis, reduces allergy have
been studied for decades. Allergen-specific immunotherapy
for allergic rhinitis and bee venom allergy is thought to
induce peripheral T cell tolerance, modulate the thresholds
for mast cell and basophil activation, and decrease IgE-
mediated histamine release [17]. By contrast, the mecha-
nisms by which immunotherapy for food allergy might work
are much less studied and are very poorly understood [18].
Routes of immunotherapy
Multiple protocols have evaluated the role of food immuno-
therapy, using different routes of administration. Initially,
subcutaneous immunotherapy to food was used, but was
associated with a very high rate of systemic reactions
(39 %) [19], which halted enthusiasm for this approach.
Over the past 10 years, oral immunotherapy (OIT) and more
recently sublingual immunotherapy (SLIT) [2027] or both
together [28] have been evaluated. In SLIT, a food extract is
placed under the tongue and then either swallowed or spit
out, while in OIT, the food is ingested. Both therapies rely
on administering a small dose first, followed by increasing
amounts during the build-up phase to reach a maintenance
dose that is usually administered daily. While many of these
studies require several months before reaching the
maintenance phase [2932], rush desensitization has been
evaluated in others [25, 3338]. More recently, epicutaneous
immunotherapy trials, which consist of applying the food
allergen as a patch on the skin, have been launched [39].
Food desensitization has been studied to different foods,
including cow's milk [28, 31, 34, 40], hen's egg [36, 41],
peanut [26, 29, 30, 32, 38], hazelnut [25, 27], kiwi[23, 24],
and peach [2022]. In addition, one study examined the role
of anti-IgE mAb (omalizumab) as an adjunct therapy to milk
OIT, which reduced allergic reactions that occurred during
the desensitization process [33] (discussed in the following).
Based on the promising findings of this study with omali-
zumab, three additional trials are being conducted to evalu-
ate the effect of anti-IgE mAb as an adjunct therapy to food
OIT, one with milk OIT (Mt Sinai) and two others with
peanut OIT (Duke University and Boston Children's Hospi-
talHarvard Medical School) (clinicaltrials.gov).
Tolerance versus desensitization
The ultimate goal of food allergy immunotherapy is cure,
resulting in permanent tolerance, as defined by the absence
of symptoms after ingestion of the food even after pro-
longed and/or erratic periods of avoidance. Usually, howev-
er, only desensitization is achieved, i.e., the patient is able to
ingest the food without reactions, but only while remaining
on maintenance dosing. True tolerance to foods after desen-
sitization has been evaluated in only a few studies, with
approaches varying from stopping the food for 2 weeks to a
few months, followed by an oral food challenge (OFC) [23,
27, 28, 38, 42, 43]. As we will discuss in this review, the
outcome of these different studies suggest that, while desen-
sitization in the setting of food allergy can be achieved in
most cases, some patients regain sensitization after interrup-
tion of food intake. We will review the different immuno-
modulatory changes that have been described with
successful food desensitization.
Evaluation of tolerance
The details of multiple studies of food immunotherapy using
different protocols have been reviewed elsewhere [4446].
Very few trials have evaluated the development of tolerance,
which may be affected by different factors, including the
route of immunotherapy, the maintenance dose, the length
of the maintenance phase, the food-specific IgE level, and
intercurrent illness.
In one open label study, 21 children aged 510 years
received cows milk oral immunotherapy (OIT) over a mean
period of 201 days [31]. Fifteen children (71.4 %) achieved
a daily intake of 200 ml of milk during a 6-month period,
Semin Immunopathol
while three of 21 children (14.3 %) tolerated 4080 ml/day,
and the other three (14.3 %) failed the desensitization. At the
final visit, the children who tolerated milk were advised to
take cow's milk and/or dairy products ad libitum. Four years
later, in a follow-up study [47], 9 of the remaining 14
patients who were desensitized totally to milk were consum-
ing it daily without interruption, taking about 250 ml of
cow's milk (corresponding to ~ 8 grams of milk protein)
and its derivatives freely, and four were either eating other
dairy products or ingesting milk occasionally. Interestingly,
one patient stopped taking milk for a month secondary to a
viral illness that occurred 6 months after the desensitization
period. When milk consumption was resumed, he developed
urticarial and asthma symptoms, indicating that, even after
successful desensitization, food allergy can return when the
food is stopped for a few weeks, even after 6 months of
maintenance food ingestion.
In an open label pilot study of egg OIT, Buchanan et al.
enrolled seven children (median age 48 months) with a
history of non-anaphylactic allergy to egg. After a modified
rush desensitization followed by a build-up phase to 300 mg
of egg protein, patients remained on a 2-year maintenance
phase [36]. Four patients passed a DBPCFC with 8 g of egg
protein, and all patients tolerated significantly more egg
protein during DBPCFC than at study onset. Interestingly,
only two of four patients who passed the DBPCFC were
able to tolerate the full amount of egg 34 months off OIT.
One patient reacted to as low as 24 mg, and the others to 2 g
of egg protein. This indicated that, even after 2 years of OIT,
desensitization may be lost after few months off of the food,
suggesting that maintenance with higher daily doses of food
may be required in order to achieve a more durable desen-
sitized state. In addition, although a state of tolerance may
have been achieved in two patients, natural tolerance may
have developed spontaneously given that the study was over
24 months and that egg allergic patients are known to
become tolerant to egg with time [7]. In a follow-up study,
the effects of higher maintenance dosing were investigated
[48]. The mean egg-white-specific IgE in enrolled patients
was 18.8 kU/l. After desensitization and daily intake of a
maintenance dose of 300-mg egg protein for 4 months,
patients with serum egg-specific IgE <2 kU/l underwent an
oral food challenge to egg, and the dose was increased
according to the highest tolerated dose. Cycles of mainte-
nance for 4 months followed by food challenges were con-
tinued until a maximum dose of 3.6 g/day was achieved.
Patients were then followed every 4 months on this dose,
and whenever egg-specific IgE < 2 kU/l, OIT was stopped,
and DBPCFC was performed with up to 10 g of egg protein.
All patients passed the challenge and were taken off OIT for
4 weeks, then successfully passed a DBPCFC. This study
suggested that, with higher maintenance doses, a state of
desensitization can be maintained when the food ingestion is
interrupted for 4 weeks. However, it is not clear whether
these subjects have reached a permanent state of tolerance.
In addition, the study also suggested that low levels of food-
specific IgE level may indicate tolerance.
Blumchen et al. enrolled 23 peanut-allergic pediatric
patients (median age 5.6 years) who underwent a first con-
firmatory DBPCFC at baseline (threshold dose for reaction
< 25 mg peanut protein) [49]. The median peanut-specific
IgE was 95.6 kU/l (range 32,071 kU/l). Subjects under-
went in-hospital rush desensitization for up to 1 week and
then a dose escalation over a median of 7 months to reach a
maximal target maintenance dose of 500 mg. Maintenance
phase lasted for a median of 8 weeks and was followed by
2 weeks of peanut avoidance. At the final DBPCFC, patients
tolerated a median of 1 g compared to 0.19-g peanut at
baseline prior to OIT. Therefore, after food interruption for
2 weeks, peanut desensitization was still maintained. As in
other studies, the effect of longer period of food interruption
remains unclear.
Overall, sublingual immunotherapy (SLIT) for food al-
lergy has been evaluated in far fewer studies compared to
that for OIT. The limitations of SLIT is that the maximal
dose of the food is dependent on the small volume that can
be administered sublingually, therefore limiting the maxi-
mum dose that can be achieved, which may limit consisten-
cy in the beneficial outcome. The first case report of food
SLIT described a 29-year-old woman with severe anaphy-
laxis on exposure to small amounts of kiwi fruit [24].
During SLIT, the dose of kiwi extract was increased over a
5-week period to a maintenance dose of 1 ml, during which
time she experienced significant allergic reactions. A main-
tenance dose of 1-cm
3
piece of kiwi was continued daily for
about 5 years, at which time it was discontinued for 4 months
because of severe tonsillitis [23]. She was then challenged
with 1-cm
3
cube of fresh Kiwi, which she tolerated. This
study demonstrated that, after 5 years of maintenance ther-
apy, the desensitization effect persisted even after a 4-month
interruption of food exposure, suggesting that a state of
tolerance could be maintained off of the food for at least
4 months.
Most recently, Keet et al. explored the efficacy of milk
SLIT versus SLIT followed by OIT. Thirty children aged 6
17 years received either SLIT alone to 7-mg maintenance
dosing, SLIT to 3.7 mg, followed by OIT to 1-g mainte-
nance dosing, or SLIT to 3.7 mg followed by OIT to 2-g
maintenance dosing [50]. After 1.4 years of maintenance
therapy, 10 % in the first group, 60 % in the second group,
and 80 % in the third group passed an 8-g oral challenge,
indicating that SLIT/OIT is significantly more efficient than
SLIT alone in desensitizing patients. However, allergic reac-
tions were much more common in the OIT versus SLIT
alone groups. Moreover, 10 % of patients in the OIT groups
withdrew due to adverse effects. To evaluate for tolerance,
Semin Immunopathol
the 15 patients who passed the OFC were taken off of
maintenance dosing for 6 weeks. Patients in the second
group (50 %) and 38 % in the third group regained milk
reactivity, indicating that the desensitization status may be
lost quickly after stopping oral dosing, despite a long main-
tenance period. This study is consistent with the findings of
Vickery et al. and egg allergy [48], suggesting that higher
maintenance dosing may lead to a more durable desensiti-
zation state.
It remains unclear why food immunotherapy is more
successful in some patients, why others are resistant to
desensitization, and why allergic reactions develop during
desensitization. Contributing factors may include subopti-
mally controlled asthma leading to more severe reactions,
physical exertion after dosing and menstruation [51], and
higher level of food-specific IgE, perhaps indicative of
greater polarization of the immune response. In addition,
the role of psychosocial stress in exacerbating or potentiat-
ing allergic reactions to the food is unclear and possibly
underestimated. There may be a subgroup of patients who
are more resistant to desensitization and may require mod-
ified protocols including a much slower build-up phase and
later a longer maintenance period. Potentially, some of these
patients may benefit from adjunct therapy to food immuno-
therapy, such as monoclonal anti-IgE antibodies (mAb).
Furthermore, whether a state of permanent tolerance can
be achieved in the majority of patients is not known, partic-
ularly because few studies examining this issue have been
performed, and in these studies, only short periods of food
avoidance have been employed. Whether longer mainte-
nance periods and higher maintenance doses are required
for real tolerance to develop is also not yet clear. The
plethora of unknowns makes the study of the mechanisms
of food immunotherapy difficult, but important for improv-
ing these therapies.
Mechanisms of food allergen immunotherapy
The mechanisms by which food allergen immunotherapy
effectively reduces allergic symptoms are poorly under-
stood, in part, because they have been inadequately studied.
Presumably, many of the features involved in immunother-
apy for food allergy are similar to those observed in inhalant
allergen immunotherapy, although the precise mechanisms
of allergen SCIT or SLIT are still controversial and remain
to be fully elucidated. However, there are significant differ-
ences between oral and subcutaneous immunotherapy, for
example, in the doses used (in OIT, the doses are many
orders of magnitude greater than that used in SCIT). In
addition, the immunological mechanisms involved in oral
versus sublingual immunotherapy may differ substantially.
Furthermore, the mechanisms involved with different food
desensitization protocols may be quite distinct, due to differ-
ences in the rapidity of dose escalation and in maintenance
doses achieved.
Mechanisms in development of allergic diseases
The mechanisms of food desensitization and tolerance must
be understood in the context of the underlying mechanisms
of the disease; the understanding of which has evolved
considerably over the past several years. For example, early
cutaneous exposure to food protein through a disrupted skin
barrier has been suggested to lead to allergic sensitization,
while early oral exposure to food allergen may induce
tolerance [52]. This hypothesis is currently being tested in
two randomized controlled trials (learning about peanut
allergy (LEAP) study and the enquiring about tolerance
(EAT) study). Classically, the development of food allergy
has been viewed as an inappropriate Th2 response to foods,
associated with increased allergen-specific IgE production,
and an increase in the number of allergen-specific Th2 cells
[18]. Clinically, patients often develop reactions with two
phases, one early and one late. The early phase response is
due to mast cell degranulation mediated by allergen-specific
IgE leading to the release of preformed and newly synthe-
sized mediators including histamine and leukotrienes, which
trigger symptoms of immediate type hypersensitivity. The
late phase reaction develops 48 h after the immediate phase
response and involves the development of complex effector
functions related to tissue inflammation and injury, with the
infiltration of allergen-specific effectors cells, such as Th2
cells and Th9 cells, as well as eosinophils and basophils
[53]. In the skin, the late phase response is characterized by
significant swelling, pruritis, erythema, and warmth; in the
lungs, the late phase response is associated with a significant
reduction in pulmonary function that is difficult to reverse
and that persist for hours. The late phase response is also
associated with the development of airway hyperreactivity, a
prominent feature of chronic asthma. The specific symp-
toms of the intestinal late phase response are not well
described, but may involve increased intestinal permeability,
vomiting, and diarrhea.
Th2 and Th9 cells, like Th1, Th17, Th22, and inducible
T
Reg
cells, comprise subsets of, and derive from naive,
CD4
+
T cells. These subsets differentiate from nave CD4
+
T cell depending on conditions present when antigen is
initially introduced. Th2 cells produce IL-4, IL-5, IL-9,
and IL13 [5355], which orchestrate the allergic inflamma-
tory response. Th9 cells secreting IL-9 appear to be a dis-
crete T helper cell subset and can be induced to develop by
the presence of TGF- and IL-4 in both mice and humans,
and this is enhanced by the presence of IL-25. IL-9 enhances
the growth of mast cells and can lead to inflammation in the
Semin Immunopathol
lung and intestines, including intestinal anaphylaxis. IL-9, in
combination with TGF-, can induce the development of
Th17 cells.
Th17 cells represent another recently described cell type,
frequently found at epithelial cell surfaces. Th17 cells, in-
duced by the presence of TGF-, IL-6, and IL-1, produce
IL-17 and IL-22 and protect against bacterial infection by
enhancing the recruitment of neutrophils. Absence of IL-17
function in humans is also associated with severe fungal
infections in the skin, whereas overproduction of IL-17 is
associated with autoimmune diseases such as inflammatory
bowel disease and psoriasis. IL-17 is also found in the lungs
of patients with severe asthma, in association with neutro-
phils, and in the skin of patients with chronic atopic derma-
titis. Th17 cells produce IL-22, which is also produced by
Th22 cells. Th22 cells only produce IL-22, which is an IL-
10 cytokine family member that plays an important role in
the lungs, skin, and intestines by inducing the production of
anti-microbial peptides and by promoting the survival of
epithelial cells in the lungs, gut, and liver. However, it
may also play a pathological role in psoriasis, possibly by
potentiating the role of IL-17. IL-22 levels are also increased
in the skin of patients with atopic dermatitis [56].
T
Reg
cells are thought to down-regulate all of the afore-
mentioned T effector cell subsets by producing anti-
inflammatory cytokines such as IL-10 and TGF- [57,
58]. There are two main types of T
Regs
cells: the first one
is called natural T
Reg
(nT
Regs
) cells and is selected in the
thymus as Foxp3
+
CD4
+
CD25
+
T
Regs
cells. These nT
Regs
cells constitute approximately 1015 % of peripheral blood
lymphocytes and prevent the development of autoimmune
disease. The other T
Reg
cell type is referred to as antigen-
specific or inducible T
Regs
(iT
Regs
) cells and is generated in
the periphery following antigen exposure [59]. iT
Regs
can be
further subdivided into Foxp3
+
iT
Regs
cells and IL-10
+
Tr1
cells [59, 60]. iT
Regs
cells can not only suppress Th2 cells,
but can also limit the function of mast cells, basophils,
eosinophils, and dendritic cells. iT
Regs
are able to inhibit
mast cell degranulation by an OX4-OX-40 Ligand interac-
tion. By producing IL-10 and TGF-, they may also induce
IgG4 and IgA production and regulate allergen-specific-IgE
[6164].
The important role of Foxp3
+
T
Reg
cells in allergy is
highlighted by the fact that Foxp3 mutant mice develop an
intense multi-organ inflammatory response associated with
allergic airway inflammation, significant hyper IgE, eosin-
ophilia, and dysregulated Th1 and Th2 cytokine production
[65]. Severe allergic inflammation is a cardinal manifesta-
tion of loss-of-function Foxp3 mutations in humans, where
affected subjects develop multiple food allergy, atopic der-
matitis, asthma, increased IgE levels, and eosinophilia [66].
The specific role of iT
Reg
cells in allergy is highlighted by
the observation that mice deficient in iT
Reg
cells, but not
nT
Reg
cells, spontaneously develop pronounced Th2 type
pathologies in the gastrointestinal tract and lungs [67].
iT
Regs
cells inhibited allergic eosinophilia and Th2 cytokine
expression in murine lung, indicating that iT
Regs
cells play
an important inhibitory role in airway inflammation [68].
Murine studies also suggest that oral tolerance does not
require CD4
+
Foxp3
+
nT
Reg
cells; on the other hand, the
establishment of oral tolerance correlates with the de novo
induction of antigen-specific CD4
+
Foxp3
+
iT
Regs
[69]. Fi-
nally, the establishment of iT
Reg
cells may require specific
intestinal microflora [70], as is discussed in another chapter
in this series.
In humans, the number of local Foxp3
+
CD25
+
CD3
+
cells
in the nasal mucosal increases after allergen immunother-
apy, and their up-regulation is associated with clinical effi-
cacy and suppression of seasonal allergic inflammation [71,
72]. IL-10 down-regulates T cells by blocking CD2, CD28,
and inducible co-stimulator (ICOS) co-stimulatory signaling
[73]. IL-10 was also shown to reduce pro-inflammatory
cytokine release from mast cells. In addition, IL-10 down-
regulates eosinophils and suppresses IL-5 production by
resting Th0 and Th2 cells [74, 75]. TGF- inhibits the
function of both Th1 and Th2 cells and induces the conver-
sion of naive CD4
+
CD25
-
T cells into CD4
+
CD25
+
T cells
by inducing the expression of Foxp3 [76].
Innate immunity in allergy
While allergen-specific CD4
+
T cells play a critical role in
regulating allergy in the gastrointestinal tract, newly de-
scribed innate immune mechanisms also contribute to food
allergy. Three recently described innate cytokines, produced
by intestinal epithelial cells, greatly enhance Th2 responses.
The first, called thymic stromal lymphopoietin (TSLP), has
been shown to be highly increased in the skin and blood of
patients with atopic dermatitis [77, 78] and in patients with
eosinophilic esophagitis and asthma. TSLP, an IL-7-like
cytokine, alters dendritic cells, causing them to selectively
induce allergen-specific Th2 cells. Moreover, TSLP appears
to directly enhance basophil hematopoiesis in a pathway
that is distinct from that induced with IL-3 [79]. Selective
expression of IL-13 in the skin of mice caused an atopic
dermatitis phenotype, and the condition was associated with
enhanced production of TSLP [80]. Elimination of TSLP
signaling significantly diminished the allergic asthma
responses, immune cell production of Th2 cytokines (IL-4,
IL-13), and serum IgE. In mouse models of food allergy, the
presence of TSLP is required to amplify Th2 responses. In
humans, TSLP polymorphisms are highly associated with
eosinophilic esophagitis and with food allergy.
IL-25, an IL-17-like cytokine (also called IL-17E), is
another innate cytokine produced by intestinal epithelial
Semin Immunopathol
cells. It is found in the lungs of patients with asthma and is
associated with allergen sensitization in humans. IL-25 also
enhances the growth and differentiation of basophils and
mast cells. In addition, increased IL-25 production by moth-
ers was associated with food sensitization in the child. IL-33
is the third recently described innate cytokine important in
allergic diseases. IL-33 is also produced by intestinal epi-
thelial cells, by lung epithelial cells, and by alternatively
activated macrophages. It is a member of the IL-1 cytokine
family and is found in the blood of patients undergoing
anaphylaxis [81], in the skin of patients with atopic derma-
titis, and in the lungs of patients with severe asthma. The
genes for IL33 and its receptor ST2 are highly associated
with asthma, and both are highly expressed in the intestines
during helminth infections in mice, suggesting that they may
play an important role in food allergy.
The importance of TSLP, IL-25, and IL-33 in allergic
disease became clear with the discovery 2 years ago of a novel
innate lymphoid cell type called nuocytes, or natural helper
cells, or innate lymphoid type 2 cells [82]. Nuocytes are non-
T, non-B cells that do not express mature hematopoietic
lineage markers, but produce large quantities of IL-5 and Il-
13. Importantly, TSLP, IL-25, and IL-33 greatly enhance the
growth and activation of nuocytes. They have been implicated
in immune responses in the gut against helminth infections
[83]. In addition, nuocytes have been found in the lungs of
mice and in humans [84, 85]. Although their role in food
allergy has not yet been determined, it is likely that they
may amplify Th2 responses, as they do in the lungs.
In summary, the mechanism leading to allergic diseases is
complex and involves multiple pathways; some of which have
only been discovered recently. Although it is clear that food
immunotherapy has a beneficial clinical effect, the immuno-
modulatory changes induced by this modality have not been
thoroughly studied in terms of all of these pathways.
Immunomodulation in food immunotherapy
The known immunomodulatory changes induced by food
immunotherapy include suppression of mast cells and baso-
phils, the generation of allergen-specific IgG-4 blocking
antibodies, the down-regulation of effector cells (antigen-
specific IgE producing cells and allergen-specific Th2 cells),
and the induction of T cell tolerance and its associated
changes in cytokine secretion. We will discuss all of these
mechanisms.
Early effects: mast cells and basophils suppression
During the initial phases of food allergen-immunotherapy,
allergen-specific IgE levels and IgE-mediated skin
sensitivity wheal size often increase, although these levels
decrease after 12 years of immunotherapy [86, 87]. How-
ever, the beneficial clinical effects are seen much sooner,
well before IgE levels drop, as treated individuals tolerate
increasing amounts of the pertinent food. A similar finding
has been observed in subcutaneous immunotherapy with bee
venom or with acute desensitization with drugs, where a
decrease in mast cell and basophil degranulation activity is
observed early during the desensitization process [17]. This
effect on mast cells and a clinical protection against bee stings,
and its discrepancy with skin test reactivity are not yet under-
stood, but may be related to the dose of antigen seen by the
mast cell and to piecemeal release of small amounts of
mediators, which somehow increases the threshold of activa-
tion of mast cells and basophils [8890]. An inhibitory hista-
mine receptor (HR2) may also be involved in rapidly
inhibiting the function of mast cells and basophils. Thus, mast
cell activation (skin test reactivity) performed in OIT studies
after maintenance dosing has been achieved shows a decrease
in food-specific skin prick test (SPT) wheal size compared to
baseline [26, 28, 30, 49, 91]. In another study, 12 months after
completing a peanut SLIT protocol, SPT was significantly
reduced in the treatment group compared to that done at
baseline, with a median wheal size of 4 mm in the former
and 11 mm in the latter, indicative of a decrease in mast cell
reactivity after peanut SLIT.
Studies of mast cell/skin tests during food immunother-
apy generally correlate with analyses of peripheral blood
basophils. For example, Jones and co-workers found that
basophil activation decreased significantly 6 months into
peanut OIT, as did skin test reactivity [30]. Similarly, baso-
phil reactivity diminished with peanut OIT, as demonstrated
by the number of activated CD63
+
basophils appearing after
in vitro stimulation with peanut extract [26]. In patients who
underwent milk OIT combined with omalizumab as an
adjunct therapy, milk-induced basophil activation was re-
duced, as demonstrated by examination of basophil expres-
sion of CD203c and CD63, histamine release, and Syk
expression after in vitro allergen challenge [92]. Initially,
basophil inactivation to all allergens was due to omalizumab
treatment and the clearance of antigen-specific IgE from the
basophil surface. However, after omalizumab was discon-
tinued (after week 16), only milk-specific (but not egg or
cashew-specific) basophil unresponsiveness persisted, sug-
gesting that milk desensitization exclusively reduced milk-
specific basophil degranulation, presumably related to a
reduction in food-specific IgE or IgG. The reduction in
milk-specific basophil degranulation after discontinuation
of omalizumab treatment correlated with a reduction in the
milk-specific skin test reactivity, consistent with a reduction
in milk-specific IgE production.
On the other hand, in a study comparing SLITwith SLIT/
OIT, Keet et al. found that, while cows milk SPT reactivity
Semin Immunopathol
was reduced over time, as did milk-specific IgE in the OIT
group, allergen- or anti-IgE-induced basophil histamine re-
lease did not fall at any point in the study [28]. This suggests
that skin testing may have greater sensitivity compared to
basophil histamine release. Interestingly, constitutive ex-
pression by basophils of CD203c (a basophil activation
marker) was reduced after immunotherapy, and subjects
who had an increased constitutive basophil expression of
CD203c early in therapy had a poorer outcome later in the
study.
These studies together suggest that food-specific immu-
notherapy can reduce allergen-specific mast cell and baso-
phil degranulation, and skin test reactivity at late time
points, in part, due to late reductions in allergen-specific
IgE production. Larger studies are needed to clarify the early
effects of food immunotherapy on mast cells and basophil
activation, and their role in the development of clinical
desensitization and possibly tolerance.
Oral and intestinal mucosa
The mechanism of food desensitization may be partly de-
pendent on the route of dose administration, as observed
with SLIT versus OIT/SCIT. The oral route may be inher-
ently associated with tolerance, presumably because oral
intake is primarily associated with nutrient absorption, even
in the face of high exposure to bacteria and potential infec-
tion [93]. In SLIT, Langerhans cells within the oral mucosa
take up antigen, which is initially recognized by allergen-
specific IgE bound to surface FcR1 (the high-affinity IgE
receptor) [94, 95]. These cells also express high levels of
MCH class I and II as well as co-stimulatory and co-
inhibitory molecules. Scadding et al. speculated that Lan-
gerhans cells and possibly other mucosal dentritic cells
migrate to regional lymph nodes where the antigen is pre-
sented to T cells, leading to the development of anti-
inflammatory allergen-specific Th1 or T
Reg
cells [93]. These
cell types then have the capacity to inhibit Th2-mediated
inflammation, particularly in non-allergic individuals. Pro-
duction of IL-10 and TGF- by oral Langerhans cells has
been shown to enhance the development of IL-10, TGF-
producing T
Regs
cells after grass SLIT [72]. In addition,
ligation of TLR4 may enhance IL-10 production of Langer-
hans cells [94] and contribute to the induction of T
Reg
cells.
Other factors that contribute to the natural capacity of the
gastrointestinal track to induce tolerance include the capac-
ity of intestinal epithelial cells and monocytes to produce
IL-10 and TGF- [96, 97], which enhance T
Reg
cell gener-
ation [98], and the production of antigen-specific IgA and
secretory IgA (S-IgA) in the intestines, which can reduce
absorption of undigested antigens at mucosal surfaces
through a mechanism known as immune exclusion, thereby
preventing inflammatory responses [99]. Thus, Scadding et
al. found that sublingual grass pollen immunotherapy was
associated not only with increases in sublingual Foxp3
+
Treg cells but also elevated allergen-specific IgA and IgG4
[100]. Similarly, another recent study on peanut SLIT
showed that salivary levels of peanut-specific IgA increased
significantly for most subjects receiving SLIT but not for
subjects receiving placebo [101].
B cell tolerance and modulation of specific IgE and IgG4
In most studies of OIT, regardless of the variation between
protocols, a significant rise in food-specific IgG4 levels
have been observed [25, 30, 36, 102]. In addition, in the
majority of the trials, food-specific IgE initially increased
for several months after initiation of food OIT or SLIT, but
then decreased either to baseline level or lower by the end of
the study [26, 30, 48]. After peanut OIT, IgE complex
formation was inhibited by serum factors in an IgE-
facilitated allergen binding assay [30]. On the other hand,
Shripak and colleagues did not find any significant change
in milk-specific IgE levels after 34 months of milk OIT
maintenance therapy though it did increase in some patients.
However, milk IgG and particularly IgG4 levels increased
significantly in patients in the active treatment group com-
pared to baseline (by a median 764 % for IgG4), while there
was no change in the placebo group [40]. Consistent with
the findings of others, Blumchem et al. found that there was
a significant reduction in peanut SPT wheal size and an
increase in peanut-specific IgG4 after peanut OIT [49].
However, 2 weeks after discontinuing maintenance peanut
therapy, peanut skin test wheal size increased. In addition,
there was a small but significant drop in peanut-specific
IgG4 levels. Interestingly, however, many (but not all)
patients passed the DBPCFC after 2 weeks of peanut inges-
tion interruption. It is not known whether the desensitization
state would have been maintained if the food interruption
were continued for a longer period of time. The drop in
peanut-specific IgG4 levels suggests that there may be a role
for food-specific IgG4 in maintaining desensitization and
possibly tolerance and that a longer maintenance phase
(months and likely years) may be required to maintain
important immunological changes that sustain immunolog-
ical tolerance.
The rise in allergen-specific IgG subtypes has been studied
in many clinical trials of food and inhaled allergens, but its
role in immune modulation remains controversial. In many
studies of allergen SCIT, IgG1 and particularly IgG4 levels
increase 10100 folds [103, 104], but the concentration of
allergen-specific IgG does not always correlate with clinical
improvement [105, 106]. IgG4 is a non-inflammatory, non-
complement binding isotype that is thought to capture the
Semin Immunopathol
allergen before it reaches the effector cell IgE, therefore pre-
venting the activation of mast cells and basophils. This could
lead to a competition for allergen biding or blocking effect
[107]. However, recent studies suggest that the beneficial
effects of allergen-specific IgG are not solely dependent on
the level of IgG, but rather on their blocking activity and
affinity or the ability to bind to the inhibitor FcRIIB on
antigen-presenting cells [108, 109]. Interestingly, while one
IgGmolecule against a single epitope on the Feld1 was able to
inhibit the degranulation of mast cells and basophils in
patients with cat allergy, a combination of two or three differ-
ent IgGs had a greater inhibitory effect. The increased inhib-
itory activity of several antibodies might be the result from
stronger crosslinking of FcgRIIB by higher-order allergen-
antibody complexes [110]. Alternatively, the effectiveness of
allergen-specific IgGmay be dependent on the IgE/IgG4 ratio,
since allergen-specific IgG4/IgE ratios were found to be about
thousand times higher in non-allergic beekeepers compared
with bee venom allergic individuals [111]. The decrease in
IgE/IgG4 ratio during immunotherapy may be secondary to
IL-10 up-regulation production, which decreases IL-4 induced
IgE switching and increases IL-4 induced IgG4 production.
Further studies are required to evaluate the role of IgG, IgG4
levels in food immunotherapy desensitization and induction
of food tolerance.
Immune deviation, T
Reg
cells, and T cell tolerance
Peripheral Tcell tolerance is characterized by the one or more
of the following: the deletion of allergen-specific T effector
cells, anergy in allergen-specific effector T cells, or the gen-
eration of allergen-specific T
Reg
cells. These events together
or alone result in limiting the function of food-specific Th2
cells, mast cells, and other allergic effector cells, and are
thought to be essential steps for successful allergen-specific
immunotherapy. The few studies that evaluated Tcell changes
during and after food immunotherapy have not provided
consistent results, and therefore, the role of immune deviation
and T cell tolerance remains controversial.
Allergen-specific iT
Reg
cells have been described to devel-
op in the context of SCIT for aeroallergens and bee venom,
using doses that are generally <50 g. In the context of food
allergy, iT
Reg
cells have been observed, for example, in
patients who are tolerating products containing heated milk.
In such patients, a significantly higher percentage of prolifer-
ating casein-specific CD25
+
CD27
+
T
Reg
cells was present
than in subjects with milk allergy [112]. The casein-specific
T
Reg
cells were found to be FoxP3
+
CD25
hi
CD27
+
, cytotoxic
T lymphocyte-associated antigen 4
+
, and CD45RO
+
CD127
-
and were derived from circulating CD25
hi
T cells. Depletion
of the CD25
hi
cells before in vitro culture significantly en-
hanced casein-specific effector T cell expansion. Their
depletion causes the enhanced proliferation of casein-
specific, effector T cell proliferation, demonstrating that they
are functionally suppressive. Finally, these cells were found to
be capable of suppressing the proliferation of CD4
+
Tcells in a
mixed lymphocyte response. These results are consistent with
the possibility that iT
Reg
cells develop when exposure to the
particular food is relatively low.
In OIT, where the doses of the food range from very low
to very high, Jones and co-workers found that the secretion
of IL-10, IL-5, IFN-, and TNF- increased over a period
of 6 to 12 months after peanut OIT [30]. The number of
FoxP3
+
Tcells observed in cultures of peripheral blood cells
stimulated with peanut increased until 12 months and de-
creased thereafter. An increase in peanut-induced inflamma-
tory cytokines/chemokines IL-5, IL-1, TNF-, and MIP-
1 and growth factors G-CSF and GM-CSF was observed.
In addition, microarray analysis of resting T cells showed
down-regulation of genes in apoptotic pathways. In another
study, Varshney et al. found that peanut OIT subjects had an
increase from baseline of the ratio of FoxP3
hi
/FoxP3
intermediate
CD4
+
CD25
+
T
Reg
cells in cultures stimulated for 7 days
with peanut antigen, from cells taken at 12 months after
initiation of peanut OIT (at the time of the DBPCFC). This
increase in the number of T
Reg
cells, some of which may
be peanut specific, was not observed in placebo-treated
patients [29]. IL-5 and IL-13 decreased significantly from
baseline, and there was a transient increase in TGF- at
9 months that decreased to baseline at DBPCFC. Although
there was no change in IL-10 or INF- levels, these studies
suggest that 12 months of peanut OIT changes the function
of peanut-specific T cells and may increase the number of
peanut-specific T
Reg
cells, at least transiently.
On the other hand, Blumchen and co-workers found that,
9 months after the initiation of peanut OIT, there was no
evidence for an up-regulation of Th1 or T
Regs
cells. They,
however, observed a down-regulation of IL-2, IL-4, and IL-
5 cytokine production from peanut-stimulated PBMCs com-
pared to baseline, suggesting a skewing away from a Th2
response [49]. These findings were peanut specific, as no
such changes were found with the milk-specific response.
However, there was no difference in INF-, TNF-, and IL-
10 production. These findings suggested that clinical im-
provement might be secondary to clonal anergy or clonal
deletion [113, 114]. After discontinuing peanut for 2 weeks,
while these changes were still noted in the majority of the
patients, four subjects showed an increase in IL-2 produc-
tion almost returning to baseline value. However, these
changes did not correlate with the clinical outcome of the
final DBPCFC or the period of time necessary to achieve the
maintenance OIT dose.
Enrique et al. found that, after hazelnut SLIT, in which
the doses are relatively low, there was a significant increase
of IL-10 levels [27]. On the other hand, 12 months after peanut
Semin Immunopathol
SLIT, IL-5 level was significantly lower in the treatment group
compared to placebo, and no significant differences between
the two groups were found in IL-10, INF-, or IL-13 levels
[26]. In addition, while an increased T
Reg
cell number was
seen in the active treatment group compared to the placebo
group, this result did not reach statistical significance. These
findings were in contrast with what has been observed in grass
SLITimmunotherapy, where an increased production of IL-10
and TGF- by oral Langerhans cells and an increased number
of IL-10 and TGF- producing T
Regs
cells were reported [72].
The authors postulated that it is possible that peanut SLIT may
preferentially induce nFoxp3
+
T
Regs
cells, which mediate their
effect more via cell-to-cell contact than cytokine secretion,
unlike type iT
Regs
that are hypothesized to be IL-10 or TGF-
producing cells [72].
After egg OIT, Vickery and co-workers did not find
statistically significant changes in IL-10, TGF-, and L-
13/INF- ratio nor in egg-specific CD4
+
CD25
hi
cell expres-
sion [48]. On the other hand, Itoh and co-workers found a
significant change in Th1/Th2 ratio 6 months after rush
hen's egg desensitization, but the changes were not signifi-
cant at 12 months [102]. Paradoxically, serum IL-10 level
decreased and plasma TGF-1 level increased at 6 and
12 months compared to baseline. There were no changes
in INF- and IL-4 levels.
OIT in combination with omalizumab
When milk OITwas performed in combination with omalizu-
mab, patients with very significant milk allergy (the mean
milk-specific IgE was 98 kU/l) could be desensitized rapidly
with relatively few allergic reactions [115]. At the end of the
study, long after omalizumab was discontinued, 82 % of
patients tolerated a dose of 8 g of milk protein, compared to
36 and 42 % in other studies of severe milk allergy [34, 40].
However, within a week of the initiation of milk desensitiza-
tion, CD4
+
T cell proliferation was strikingly decreased com-
pared to baseline. The dose of milk, which reached 1,000 mg
within 1 week of desensitization and increased to 2,000 mg/
day over the next 710 weeks [92], rapidly reduced the milk-
specific T cell but not the tetanus toxoid T cell proliferative
response. The reduction in milk-specific proliferation was not
associated with an increase in CD4
+
Foxp3
+
T
Reg
cells nor was
it associated with increased IL-10 production, as it was not
inhibited by the presence of anti-IL-10 monoclonal antibodies
(mAb) or anti-TGF- mAb, indicating that IL-10 and TGF-
were not responsible for the decrease in the milk response.
These results suggest that milk-specific T cell anergy or dele-
tion may develop when the allergen dose is rapidly increased
during oral desensitization.
In this study, omalizumab was used only for 16 weeks, but
during this time, omalizumab may have reduced FcRI on
mast cells and basophils [116], which decreases the
responsiveness of mast cells and basophils to antigen chal-
lenge [117], and reduces mast cell and basophil survival [118].
In addition, omalizumab can decrease the interaction of IgE
with FcRII and FcRI present on antigen-presenting cells
and dendritic cells [119], which can reduce antigen presenta-
tion, interfere with the total IgE production by B cells, and
decrease the activation of Th2 cells producing IgE-stimulating
cytokines, such as IL-4, IL-5, and IL-13 [120, 121]. However,
in the study, several months after omalizumab treatment was
discontinued and after maintenance dosing was achieved, the
milk-specific CD4
+
Tcell proliferation returned. This increase
in Tcell proliferation was associated with an increase in INF-
production, associated with the return of the vigorous milk-
specific response, suggesting the development of immune
deviation towards a Th1-skewed response. A similar Th1-
like allergen-specific response was found in peanut-allergic
patients who had naturally outgrown their sensitivity [122]
and in milk-specific Peyer's patch T cells from non-allergic
individuals [123].
The different and sometimes contradictory findings be-
tween studies (e.g., with regard to T
reg
cells) may be due, in
part, to multiple factors, including differences in build-up
phase protocol, target maintenance dose, duration of mainte-
nance phase, and sometimes a variable period of food inter-
ruption. In murine studies, iT
Reg
cells are more prominent
when low doses of oral antigen are used and less prominent
when high doses are used, where deletion and anergy become
evident. Thus, food-specific iT
Reg
cells might be more likely
to be observed in protocols with slow dose escalation. In
addition, the seemingly contradictory findings may be sec-
ondary to large variations between studies in terms of the
timing of immunological evaluation during food immunother-
apy, as well as the laboratory techniques that were followed.
Larger studies are required to elucidate the role of T
Regs
cells
and the different cytokines in inducing desensitization after
food immunotherapy, and explore the possibility of develop-
ment of anergy and clonal deletion. It should also be noted that
identifying allergen-specific T
Reg
cells is difficult because
their frequency is extremely low, and special techniques,
which have only been used in a few studies, may be required.
Additional techniques, such as the use of MHC class II-
antigen peptide tetramers, may be useful in this regard. Final-
ly, it is also possible that several different mechanisms may be
involved in different situations, some involving antigen-
specific iT
Reg
cells, antigen-specific T
R
1 cells, or immune
deviation, in which the cytokine profiles of antigen-specific
T cells evolve with time.
T cell anergy
Anergy in T cells is defined as lack of responsiveness to the
antigen that can be restored with IL-2 and associated with
Semin Immunopathol
the absence of T
Reg
immunosuppressive activity [124].
In our study using omalizumab as an adjunct therapy for
milk OIT, milk-specific T cells acutely lost the capacity to
proliferate in response to milk antigen at the time of rush
desensitization. The loss in ability to proliferate was not
associated with the presence of T
Reg
cells and was partially
reversed in the presence of IL-2, suggesting that the high-
dose milk administration used for rush desensitization over
6 h resulted in the development of milk-specific T cell
anergy and possibly partial deletion [92]. Rapid reduction
in allergen-specific CD4
+
T cell responses has been ob-
served in beekeepers exposed to multiple bee stings (aver-
age cumulative antigen dose <14 mg over 7 months),
although it was not clear if the reductions were due to
anergy/deletion or the development of venom-specific T
Regs.
[125]. In grass and bee venom SCIT in which doses ranged
from 4 to 100 mcg per dose, allergen-specific tolerance was
associated with the induction of allergen-specific T
Regs
pro-
ducing IL-10 [58, 126]. It is possible that high-dose immu-
notherapy (using gram amounts of antigen) used in oral
immunotherapy leads to anergy and/or deletion of antigen-
specific CD4
+
cells, while low dose can lead to the devel-
opment of T
Regs
. It is possible, however, that the T
Regs
cells
could develop later in the course of food immunotherapy.
Additional studies will be required to evaluate the role of
anergy in reaching a state of desensitization and later toler-
ance in food IT.
Conclusions
There have been many recent clinical studies evaluating the
effects of food immunotherapy. The studies are heteroge-
neous in terms of routes and rates of administration of the
food antigen, different target maintenance dose, and dura-
tion of maintenance therapy. The definition of success also
varies between investigators, as some aim for achieving a
tolerated threshold dose during final OFC large enough to
limit allergic reactions with accidental ingestions, while
others aimed for much higher doses that would allow inges-
tions of more substantial quantities of food. In addition,
there may be a subset of patients who are resistant to food
desensitization, possibly secondary to uncontrolled asthma,
recurrent illnesses, psychosocial stressors, or due to a
higher sensitivity to food. Most studies did not include
patients with a history of severe anaphylaxis, therefore
excluding patients with more severe disease, who may re-
quire modified protocols with slower build-up and longer
maintenance phase. These patients may benefit from adjunct
therapy to food immunotherapy, such as anti-IgE mAb.
Although some studies attempted evaluation for tolerance,
most have relied on food interruption for only a few weeks.
Even with maintenance doses as long as 60 weeks, many
patients redeveloped sensitization after food interruption for
these few weeks. It is likely from the outcome of these
observations that maintenance doses may be needed for
years before permanent tolerance and therefore cure is
achieved. It is also possible that the maintenance dose and
duration may depend partly on the severity of the allergy
and possibly on food-specific IgE level. The mechanisms
underlying a successful food desensitization are still very
unclear and may involve similar mechanisms observed in
allergen SCIT and SLIT, including mast cell and basophil
suppression, food-specific IgG4 antibodies formation or
changes in food-specific IgE/IgG4 ratios, up-regulation of
natural or inducible T
Regs
cells, a skewing from a Th2 to a
Th1 profile, and the development of anergy or deletion of
allergen-specific cells. The role of Th9, Th17, Th22 cells,
and innate cytokines such as TSLP, IL22, IL-25, and IL-33,
as well innate immunity pathways such as Myd88, in intes-
tinal immunity have only recently been described and have
not been investigated in-depth in food allergy. Additional
studies will be required to more fully elucidate the mecha-
nisms by which desensitization and tolerance are achieved,
as this may also reveal biomarkers that could measure
serially to evaluate and monitor for tolerance or possibly
cure.
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